The peroral administration of drugs still represents the most commonly used method of administration. For patient compliance with peroral administration human gustatory and olfactory sense is of great importance.
Traditional dosage forms such as tablets or capsules, which are to a great extent used as carriers for the oral delivery of drugs, usually are indeed tasteless, however require in common usage, that the patient keeps at hand a fluid, with which he can take this dosage form. Because of discomfort in swallowing especially in elder patients and children, this form of intake is often problematic. Moreover, a discrete intake is hardly possible. This sometimes leads to poor compliance and can thus jeopardize the success of therapy.
Even in groups of patients with mental diseases, in which the monitoring of the actual intake of their medication is essential, the administration of conventional dosage forms such as tablets or capsules is not unproblematic. Because of their delayed resolution they can be easily removed from the mouth, without being noticed by the supervising medical personnel.
To overcome the problems described, pharmaceutical dosage forms, such as granules or oral films have been developed, which can be taken without liquid supply and which disintegrate rapidly in the oral cavity. Oral films are characterized for example by the fact that they have a low layer thickness and a large surface area, and remain stuck to oral mucosa and disintegrate very quickly in the oral cavity. They can be taken always and everywhere discretely according to the patient's needs, without the need of additional, simultaneous intake of fluid.
Oral films and methods of preparation thereof are described, for example in WO2007/009800 and WO2007/009801.
A particular problem with the administration of bitter tasting drugs in the form of an orally dispersible film poses their release in the oral cavity or on the tongue of the patient. Because of the bitter taste of the respective drugs, taking such formulations is often perceived as very unpleasant, leading to an impairment of compliance. The masking of the bitter taste of the drugs used, i. e. the flavor optimization of oral films is therefore of great importance in the development of this dosage form.
Method for taste masking in pharmaceutical preparations generally include for example the use of coatings, the production of granules, the use of sweeteners, the microencapsulation, the use of taste suppressive and taste enhancer, the preparation of solid dispersions, the use of ion exchange resins, the use of viscosity-increasing substances, the complex formation, the use of pH modifying agents, and the use of adsorbents (see for example Ayenew, Z. et al., Trends in Pharmaceutical Taste Masking Technologies: A Patent Review, Recent Patents on Drug Delivery and Formulation 2009, 3, 26-39).
Non-mucoadhesive, orally disintegrating films as pharmaceutical dosage forms are described in WO 2008/040534. The drugs released therefrom are however not absorbed via the oral mucosa. The objective in the for development of these films was instead the provision of a generic dosage form, the pharmacokinetic properties of which are similar to those of orally administered dosage forms, after the administration of which there is an absorption of the released drugs in the gastrointestinal tract, such as tablets, capsules, liquid suspensions or orally disintegrating tablets. Beside a film former the films disclosed in WO 2008/040534 may also contain flavorings, sweeteners and taste-masking agents. As taste-masking agents amino alkyl methacrylate copolymers such as Eudragit E PO and cyclodextrin are described. The list of drugs that is described in WO 2008/040534 for administration with the film formulation disclosed therein contains i. a. the following bitter tasting drugs: risperidone, sildenafil, vardenafil, sumatriptan, zolmitriptan, naratriptan, cetirizine and dextromethorphan.
In US 2003/0211136 rapidly disintegrating films for oral administration are disclosed, which are in particular characterized by the presence of a sweetener for taste masking. As suitable sweeteners, natural and artificial sweeteners are described, such as monosaccharides, disaccharides and polysaccharides, saccharin salts, sweeteners based on dipeptide, such as sweeteners derived from L-aspartic acid, and protein based sweeteners. Further suitable sweeteners are sucralose, aspartame, acesulfame potassium, neotame, saccharin, xylitol, and mixtures thereof. Bitter tasting drugs, which are mentioned in US 2003/0211136, are i. a. dextromethorphan, diphenhydramine, cetirizine and nicotine.
Another film formulation for oral administration of a bitter tasting drug is described in WO 2006/013416. Therein a complex is used for taste masking, which consists of a taste receptor blocker, a taste receptor competitor and a sweetener as well as optionally of a flavoring agent. Hydrogenated ethoxylated glycerol esters are described as suitable taste receptor blockers. The taste receptor competitor generally include substances that give a salty or a sour taste, such as citric acid and phosphoric acid or their sodium and potassium salts as well as sodium chloride and hydroxy acids, such as glycolic acid, lactic acid and tartaric acid, etc., and their salts. As sweeteners both substances are suitable whose sweetness effect occurs immediately, as well as substances whose sweetness effect occurs only delayed. Examples are saccharin, sucralose, neotame, alitame, aspartame and cyclamate, etc. for sweeteners with immediate effect as well as monoammonium glycyrrhizinate for sweeteners with delayed sweetness effect. As bitter tasting drugs dextromethorphan, chlorhexidine, guaifenesin, pseudoephedrine, caffeine, peroxides, atorvastatin, aspirin, paracetamol, diphenhydramine, doxylamine, sildenafil citrate and loperamide are disclosed in WO 2006/013416.
A polymer-based edible film formulation with sildenafil citrate, tadalafil, or vardenafil as drug contained therein is disclosed in US 2009/0047330. For taste masking the use of cyclodextrins or the encapsulation of the drugs is proposed. Besides the film formulation may also contain flavoring agents, such as menthol and the like, as well as sweeteners, such as acesulfame potassium, sucralose, aspartame and glyrrhizin.
A fundamental problem of these formulations is that the effective covering of taste of extremely bitter tasting drugs such as sildenafil, is difficult to achieve—if at all—by conventional methods, i.e. solely by the addition of sweeteners, flavoring agents, etc. This applies in particular, if drug concentrations of more than 50 or 60% by weight related to the total weight of the formulation are used. In such cases it is usually necessary to coat the particular drug in a complex method (see Section 4. Factors affecting selection of taste masking technology: A. Extend of bitter taste in Ayenew, Z. et al., Trends in Pharmaceutical Taste Masking Technologies: A Patent Review, Recent Patents on Drug Delivery and Formulation 2009, 3, 26-39).
The object of the present invention is accordingly, to provide a film formulation for oral administration that after taking in the oral cavity disintegrates quickly and which enables effective taste masking of high concentrations of extremely bitter tasting drugs contained therein and which can at the same time be produce both simply and inexpensively.
Surprisingly it has now been found that the specific combination of one bitterness masker containing one or more inorganic and/or organic salt(s) and a plurality of monocyclic monoterpenes, and one or more sweetener(s) and optionally one or more flavoring agent(s) is suitable for effective taste masking even of extremely bitter tasting drugs in films suitable for oral administration.
Likewise, it was surprisingly found that based on this combination, an acceptably tasting single-layer film or a single-layer preparation, respectively, comprising one or more film formers and one or more extremely bitter tasting drug(s) can be formed.
It was found that the bitter taste sensation induced by the one or more drug(s) formulated in a film is more intense and unpleasant, the longer the film remains in the oral cavity, i. e. the greater the retention time of the drug or the drugs is in the oral cavity. In order to minimize the intensity of the bitter taste, it is thus desirable to reduce the time period between the taking of the oral film and its complete disintegration in the oral cavity. This criterion can in general be met in that the oral film is kept very thin, i.e. has a large surface to volume ratio.
Especially very thin film formulations, however have the disadvantage that they dry out very quickly, sometimes even during film synthesis, and then lose their flexibility and become brittle. This negatively affects the manufacturing process and is also very undesirable in application. In order to ensure the flexibility necessary for manufacture and for handling by the patient, in particular of very thin film formulations, permanent moisture content in the film is thus necessary. It appeared that a water content of 2-10% w/w of the film conveys the desired flexibility.
Surprisingly it appeared that a moisture content of 2-10% w/w for sufficiently ensuring flexibility can permanently be maintained even in very thin films if the film formulation contains a special combination of sugar alcohols.
The film according to the invention or the preparation according to the invention disintegrates within a few seconds in the oral cavity. For example, the film/the preparation is dissolved by saliva or decomposed, for example a water-soluble film is dissolved. Thus, the film or the preparation can no longer be spit out. After disintegration of the film/preparation the drug is predominantly swallowed and absorbed in the gastrointestinal tract. The drug may be partially absorbed transmucosally, this is however negligible. The film/the preparation is preferably substantially free of voids, surfactants and sherbets.
The preparation of the oral films according to the invention or the preparations according to the invention further is much cheaper than the production of for example so-called melting tablets, for which a complex lyophilization process is required, or the preparation of orally dispersible formulations, in which a bitter tasting drug is taste masked in complex processes such as microencapsulation, covering or complexation.
The film according to the invention is further characterized in that it also remains flexible over a long period of time in open storage under the conditions of climate zones II-IV and does not break when applied by the patient.